Abstract:

It has been found that the combination of an antihistamine with a
corticosteroid is more effective in the treatment of atopic dermatitis
than either one used separately. The synergistic effect in some cases
results in the disappearance of the atopic dermatitis lesion within one
to five days with little or no relapse. Compositions and the methods of
utilizing these preparations are disclosed.

Claims:

1. A topically administrable formulation for the sustained remission of
atopical dermatitis in a mammal affected therewith until re-exposure to
the causative agent, having active ingredients consisting essentially of
at least one antihistamine in its nonionized form or as the
pharmaceutically acceptable salt thereof and at least one compound
selected from the group consisting of corticosteroids and glucocortico
steroids, dissolved in a pharmacologically acceptable carrier.

2. (canceled)

3. The formulation of claim 1 wherein said carrier is a polar solvent.

4. The formulation of claim 3 wherein the carrier additionally comprises a
non polar solvent in the presence of said polar solvent.

8. The formulation of claim 1 wherein the formulation is administrable as
a pump spray.

9. The formulation of claim 4 wherein the formulation is administrable as
an aerosol spray.

10. The formulation of claim 5 wherein the formulation is administrable as
a foam.

11. The formulation of claim 10 additionally comprising a propellant.

12. The formulation of claim 1 wherein the formulation is administrable as
an ointment.

13. The formulation of claim 1 wherein the antihistamine in its nonionized
form or as the pharmaceutically acceptable salt thereof salt comprises
between about 0.001 and about 5.0 wt % of the entire formulation and the
corticosteroid or glucocortico steroid component comprises between about
0.01 and about 5.0 wt % of the entire formulation.

14. The formulation of claim 13 wherein the antihistamine comprises
between about 0.02 and about 3.0 wt % of the entire formulation and the
corticosteroid or glucocortico steroid component comprises between about
0.002 and about 3.0 wt % of the entire formulation.

15. The formulation of claim 1 wherein the antihistamine is selected from
the group consisting of clemastine, chlorpheniramine, triprolidine,
dextromorphan, cetirizine, fexofenadine, promethazine, montelukast,
dipheniramine and doxylamine said antihistamines being in the nonionized
form or as the pharmaceutically acceptable salt thereof.

16. The formulation of claim 1 wherein the antihistamine is selected from
the group consisting of astemizole, loratadine, and desloratidine said
antihistamines being in the non ionized form.

18. The formulation of claim 17 wherein the antihistamine is selected from
the group consisting of clemastine, chlorpheniramine, triprolidine,
dextromorphan, cetirizine, fexofenadine, montelukast, dipheniramine and
doxylamine, said antihistamines being in the nonionized form or as the
pharmaceutically acceptable salt thereof.

19. The formulation of claim 17 wherein the antihistamine is selected from
the group consisting of astemizole, loratadine, and desloratidine said
antihistamines being in the non ionized form.

20. A method of providing sustained remission of atopic dermatitis in a
mammal afflicted with same until re-exposure to the causative agent, by
applying a solution in a carrier of active ingredients consisting
essentially of at least one antihistamine in its nonionized form or as
the pharmaceutically acceptable salt thereof and a compound selected from
the group consisting of at least one corticoid and at least one
glucocortico steroid to the afflicted skin areas thereof.

21. The method of claim 20 wherein the active ingredients are applied as a
mixture.

28. The method of claim 20 wherein said formulation additionally comprises
a propellant.

29. The method of claim 26 wherein said formulation additionally comprises
a propellant.

30. The method of claim 23 wherein the formulation is administered as a
pump spray.

31. The method of claim 26 wherein the formulation is administered as an
aerosol spray.

32. The method of claim 27 wherein the formulation is administered as a
foam.

33. The method of claim 27 additionally comprising a propellant.

34. The method of claim 22 wherein the formulation is administered as an
ointment.

35. The method of claim 20 wherein the antihistamine in its nonionized
form or as the pharmaceutically acceptable salt thereof salt comprises
between about 0.001 and about 5.0 wt % of the entire formulation and the
corticosteroid or glucocortico steroid component comprises between about
0.01 and about 5.0 wt % of the entire formulation.

36. The method of claim 35 wherein the antihistamine comprises between
about 0.02 and about 3.0 wt % of the entire formulation and the
corticosteroid or glucocortico steroid component comprises between about
0.002 and about 3.0 wt % of the entire formulation.

37. The method of claim 20 wherein the antihistamine is selected from the
group consisting of clemastine, chlorpheniramine, triprolidine,
dextromorphan, cetirizine, fexofenadine, promethazine, montelukast,
dipheniramine and doxylamine said antihistamines being in the nonionized
form or as the pharmaceutically acceptable salt thereof.

38. The method of claim 20 wherein the antihistamine is selected from the
group consisting of astemizole, loratadine, and desloratidine said
antihistamines said antihistamines being in the non ionized form.

40. The method of claim 39 wherein the antihistamine is selected from the
group consisting of clemastine, chlorpheniramine, triprolidine,
dextromorphan, cetirizine, fexofenadine, montelukast, dipheniramine and
doxylamine said antihistamines being in the nonionized form or as the
pharmaceutically acceptable salt thereof.

41. The method of claim 39 wherein the antihistamine is selected from the
group consisting of astemizole, loratadine, and desloratidine said
antihistamines said antihistamines being in the non ionized form.

Description:

FIELD OF THE INVENTION

[0001]Antihistamine/corticosteroid ointment, foam or spray for the
treatment of atopic dermatitis.

BACKGROUND OF THE INVENTION.sup.[1a]

[0002]Atopic dermatitis (AD) is a common, Th2 cell-mediated, eczematous
skin disorder that affects 15% to 20% of children in developed
countries.sup.[1b] and 1% to 3% of adults..sup.[2] Epidemiologic studies
suggest that there has been a 2- to 3-fold increase in the prevalence of
AD during the past 3 decades..sup.[3] The basis for this increased
prevalence of AD is poorly understood. In 1989, Strachan.sup.[4]
postulated the "hygiene hypothesis," which proposes that allergic
diseases, such as AD, might be prevented by "infection in early childhood
transmitted by unhygienic contact with older siblings." Given the fact
that IgE-mediated allergic responses are driven by pro-inflammatory
cytokines released by Th2 cells, whereas responses to infection are
mediated by pro-inflammatory cytokines released by Th1 cells, a decreased
number of childhood infections could indeed predispose to enhanced
Th2-type allergic responses..sup.[5]

[0003]AD is typically a disease of childhood. Most adults who suffer from
chronic eczema have had nearly lifelong disease. However, a small
percentage of adults (variably estimated at 3% to 5%) may first manifest
atopic dermatitis after 18 years of age. Indeed, among studies performed
on individuals undergoing patch testing for eczematous disease,
approximately 9% of adult patients ≧18 years of age were diagnosed
with new-onset atopic dermatitis..sup.[6,7] It is noteworthy that a
significant percentage of these adult patients can present with
nonflexural involvement and/or dermatitis patterns more akin to nummular
dermatitis, prurigo nodularis, or follicular eczema..sup.[7,8]
Additionally, a significant number of "burned out" atopic children will
present in adulthood with work-related hand eczema, predominantly on the
basis of a lowered threshold for irritation. This is particularly true
among individuals with an atopic diathesis who enter into "wet work"
professions or other professions involving significant exposure to
cutaneous irritants.

[0004]Given the chronic, relapsing nature of AD and its associated, often
intense, pruritus, the disease has a significant impact on the patient's
life: social interactions are hindered, self-esteem is lowered, and sleep
disturbances are not unusual. In a study using the Dermatology Life
Quality Index to assess the effect of severe atopic eczema on the quality
of life in 92 adult patients, Finlay.sup.[10] noted that adults with
severe atopic eczema considered that having diabetes or hypertension
would be better than having eczema. Eighty percent of these patients
reported that their AD affected family life and 57% reported that the
disease hindered sexual relationships..sup.[10] Thirty-two percent of
Finlay's patients reported having lost a median of 5000 pounds in income
over the prior year because of their eczema..sup.[10] Not surprisingly,
50% of these patients would give up 2 or more hours per day in order to
have normal skin, and 74% would pay 1000 pounds or more for a
cure..sup.[10]

DISCUSSION OF THE PRIOR ART

[0005]Emollients: traditional treatments for AD have included proper skin
care and bathing habits, avoidance of triggers including irritants, and
the use of bland emollients. In clinical trials, emollients alone
demonstrated enhanced therapeutic responses.sup.[11-13].

[0006]Avoidance of food and aeroallergen Triggers: Patients with AD are
advised to avoid known triggers. IgE-mediated reactions to foods and/or
aeroallergens may exacerbate the disease however IgE-mediated reactions
to foods are an uncommon factor in the adult patient with AD.

[0007]Glucocorticosteroids

[0008]While patients with very mild AD may be controlled by avoiding
triggers and maintaining appropriate moisturization, many patients,
especially those with more moderate to severe disease, will experience
chronic and relapsing flares. Since the 1950s when they were first
introduced, topical glucocorticosteroids have been the benchmark therapy
for AD..sup.[14] In controlled trials, judicious, intermittent use (twice
weekly) of a mid-potency topical steroid has been shown to be safe and
efficacious..sup.[15,16]

[0009]The issues surrounding local cutaneous side effects from chronic
glucocorticosteroid use, including atrophy, striae, telangiectasia,
hypopigmentation, and perioral dermatitis, are well known. However, the
potential for systemic side effects following long-term, chronic steroid
use requires further study. While it is clear that inhaled
corticosteroids can result in a significant reduction in bone density;
marked suppression of the hypothalamic pituitary axis (HPA) with adrenal
suppression; and an enhanced risk for posterior subcapsular cataracts,
ocular hypertension, and/or glaucoma,.sup.[17] the risks of these
side-effects when glucocorticosteroids are used long-term topically has
not been extensively studied. The potential for topical steroids to
suppress the HPA in pediatric patients has been associated with treatment
of patients with more severe disease who are 2 years of age or
younger..sup.[18-20] Prolonged use of topical corticosteroids around the
eyes has been reported to induce open-angle glaucoma and
cataracts,.sup.[21] although controlled studies have not been performed.
Similarly, there are no studies assessing the impact of long-term
treatment with topical steroids on bone mineral density. In the absence
of these studies, it would seem well advised to counsel patients
undergoing long-term topical steroid therapy to ingest adequate calcium
and vitamin D, to undergo surveillance ophthalmic examinations, and to be
vigilant regarding signs or symptoms of iatrogenic Cushing's disease.

[0010]The Calcineurin Inhibitors

[0011]Tacrolimus.

[0012]The topical calcineurin inhibitors (tacrolimus and pimecrolimus)
work by inhibiting the activation of calcineurin in responding T cells.
The safety and efficacy of tacrolimus ointment (Protopic) in reducing the
severity of moderate to severe AD in children (≧2 years of age,
0.03% tacrolimus) and in adults (≧16 years of age, 0.1%) has been
demonstrated in a number of studies, including those assessing long-term
control of the disease..sup.[22-25] In a study of 408 adult atopic
dermatitis patients over a 4-year period (median duration of treatment
902 days), no additional adverse events from tacrolimus 0.1% ointment
were identified that had not been reported in the 12-week
trials..sup.[29]

[0013]The comparative efficacy of tacrolimus 0.1% vs topical
glucocorticosteroids has been assessed in several studies. Tacrolimus
0.1% was compared to alclometasone dipropionate 0.1% in 143 patients with
AD affecting the face and neck; tacrolimus 0.1% was significantly more
effective..sup.[26] In another trial comparing tacrolimus 0.03% and 0.1%
ointments vs hydrocortisone butyrate 0.1% ointment in 570 adults with
moderate to severe atopic dermatitis, tacrolimus 0.1% ointment was as
effective, and tacrolimus 0.03% was significantly less effective, than
hydrocortisone butyrate 0.1% ointment..sup.[28] Another study.sup.[27]
compared tacrolimus 0.1% ointment to betamethasone valerate 0.1% ointment
in 968 adults with moderate to severe atopic dermatitis of the trunk and
extremities and found that tacrolimus was significantly more effective
based on the proportion of patients that cleared or achieved excellent
improvement.

[0014]Pimecrolimus.

[0015]A number of studies have likewise evaluated the long-term safety and
efficacy of pimecrolimus (Elidel) cream 1%. The most long-term of these
studies have been performed in infants and children with moderate to
severe disease treated intermittently for up to 2 years..sup.[28-30] In a
study of 130 adults with moderate atopic dermatitis who were randomized
to receive pimecrolimus cream 1% or vehicle at the first signs/symptoms
of AD for a 6-month period, 59.7% of pimecrolimus-treated patients
experienced no flares during the study period, compared with 22.1% of
vehicle-treated patients..sup.[35] Patients in both treatment groups who
experienced a flare of dermatitis were allowed treatment with
prednicarbate 0.25% cream. It was noted that corticosteroids were
required on significantly fewer days in the pimecrolimus group compared
with the vehicle group..sup.[31]

[0016]In a similarly designed, randomized trial of 192 adults with
moderate to severe atopic dermatitis,.sup.[32]44.8% of patients in the
pimecrolimus group did not experience a flare, compared with 18.8% of
patients in the control group. Furthermore, the median time to first
flare was 144 days in the pimecrolimus group and 26 days in the control
group..sup.[32] Corticosteroid medication for flares was used on 14.2% of
the days during the 24-week treatment period in the pimecrolimus group
and in 37.2% of the days in the control group, which represented a
significant reduction in the use of steroids by the pimecrolimus
group..sup.[32]

[0017]To date, the relative potency of pimecrolimus 1% vs topical
glucocorticosteroids has been evaluated in 2 studies. In one, a phase 2,
double-blind, randomized, parallel-group, multicenter, dose-finding study
in 260 patients with moderate to severe AD affecting 5% to 30% of the
body surface area, a clear dose-response relationship for pimecrolimus
was evident: 0.2%, 0.6%, and the currently marketed 1.0% creams all were
significantly more effective than vehicle..sup.[33] When compared to
betamethasone valerate 0.1% cream, pimecrolimus 1% was not as effective
in treating nonfacial disease during the limited time (3 weeks) of this
study..sup.[33] In another randomized, double-blind, multicenter study
assessing the long-term safety and tolerability of pimecrolimus cream 1%
vs a combination steroid regimen (triamcinolone acetonide 0.1% cream for
the trunk and extremities and hydrocortisone acetate 1% cream for face,
neck, and intertriginous areas), the combined topical corticosteroid
regimen was significantly more effective than pimecrolimus cream 1% after
treatment for 1 week, 3 weeks, and 6 months..sup.[34] However, there was
no significant difference in outcomes at the end of the 12-month
study..sup.[34]

[0018]Pimecrolimus vs Tacrolimus.

[0019]In a 6-week, randomized, single-blind study of 141 children with
moderate atopic dermatitis,.sup.[35] pimecrolimus 1% cream was as
effective as tacrolimus 0.03% ointment when the proportion of children
clear or almost clear at 6 weeks was assessed. With the exception of the
results on Day 22 of the study, there was no difference between the
treatment groups in the proportion of patients reporting no or mild
pruritus..sup.[35] Only one 6-week study has compared tacrolimus 0.1% to
pimecrolimus 1% cream in adults..sup.[40] In this randomized,
investigator-blinded study of 350 patients≧16 years of age with
mild to very severe atopic dermatitis, the median percent reduction in
eczema area severity index (EASI) score was significantly greater for the
tacrolimus 0.1% ointment (74%) than for pimecrolimus 1% cream
(54%)..sup.[36]

[0020]Safety issues with calcineurin inhibitors. Despite clinical studies
(in over 19,000 patients, including more than 7000 children for both
pimecrolimus cream [data on file, Novartis Pharmaceuticals] and
tacrolimus ointment [data on file, Fujisawa Healthcare]) that showed
transient and low systemic exposure and no evidence of systemic
immunosuppression for both drugs, the US Food and Drug Administration
(FDA) issued a Public Health Advisory dated Mar. 10, 2005,.sup.[37] which
indicated its intent to require labeling changes for both Elidel
(pimecrolimus) cream and Protopic (tacrolimus) ointment that would
include placement of a black-box warning about the potential cancer risks
of these drugs. This action was based on studies (in mice, rats, and
monkeys exposed orally, and in rodents exposed topically) in which
cancers developed following exposures to these calcineurin inhibitors at
systemic levels more than 25 times higher than the maximum human exposure
following topical application. In interpreting these animal data, it must
be realized that patients with atopic dermatitis would be expected to
have considerably less daily systemic exposure to topical tacrolimus or
pimecrolimus when compared to that observed in rodents in lifetime
carcinogenicity studies, especially since the skin of the rodent is much
more permeable than that of man..sup.[38] Additionally, in the 39-week
oral gavage study in cynomolgus monkeys, where pimecrolimus at 15, 45,
and 120 mg/kg/day orally was associated with immunosuppression-related
lymphoproliferative disorders, it should be kept in mind that the highest
blood level observed following topical application of pimecrolimus 1%
cream, including in infants as young as 3 months of age with 92% of body
surface involvement, was 55 times less than the lowest level with an
effect in these monkeys (data on file, Novartis Pharmaceuticals).

[0021]The issue of lymphoproliferative diseases in association with
systemic (not topical) calcineurin inhibitors has been termed
immunosuppression-related post-transplant lymphoproliferative disorders.
These disorders constitute a spectrum of B-cell diseases, ranging from
benign polyclonal hyperplasia to malignant B-cell lymphomas, which occur
in transplant recipients receiving intensive immunosuppressive
regimens..sup.[39] Immunosuppressive transplant regimens typically
include high doses of calcineurin inhibitors (cyclosporine or tacrolimus
systemically), as well as corticosteroids, azathioprine, antilymphocytic
antibodies, and other immunosuppressive medications..sup.[40,41] In
contrast to lymphomas that occur in immunocompetent individuals,
immunosuppressive-related, post-transplant lymphoproliferative disorders
are generally treated by a reduction or cessation of the
immunosuppressive therapy..sup.[42] Furthermore, a major risk factor for
post-transplant lymphoproliferative disease is transplant-related
infection with Epstein-Barr virus..sup.[39] In immunocompetent and many
immunocompromised individuals, lymphoproliferation does not occur in
response to Epstein-Barr virus-transformed B cells due to viral specific
cytotoxic T cells and natural killer cells. To date, in clinical studies
and postmarketing reports, there have been no cases of B-cell lymphoma or
B-cell lymphoproliferative disorders associated with topical use of
either tacrolimus ointment or pimecrolimus cream. Furthermore, in
clinical studies evaluating both pimecrolimus and tacrolimus applied
topically, there has been no evidence that these agents impair dermal or
systemic immune function..sup.[29,43-45] Of note, in a 1-year study
comparing the safety and efficacy of topical corticosteroids to 1%
pimecrolimus cream in adults with moderate to severe atopic dermatitis,
individuals treated with topical steroids had a significantly higher
ingdence of bacterial infection, especially folliculitis, as well as
complicating herpes simplex eruptions..sup.[34]

[0022]In murine photocarcinogenicity studies, tacrolimus 0.1% ointment was
found to slightly, but significantly, decrease the latency time to onset
of first tumor (benign or malignant lesion>1 mm in diameter) when
compared with its vehicle (data on file, Fujisawa Healthcare). By
contrast, there was no evidence in these studies that either tacrolimus
0.03% (data on file, Fujisawa Healthcare) or pimecrolimus 1% cream (data
on file, Novartis Pharmaceuticals) enhanced the rate of
photocarcinogenicity relative to their respective vehicles.

[0023]In a study by Naylor and colleagues.sup.[46] that investigated
whether patients in the United States treated with topical tacrolimus
ointment had an increased risk for nonmelanoma skin cancer compared with
age-specific ingdences reported in the Physician's Health
Survey,.sup.[47] no evidence of an increased risk for non-melanoma skin
cancers was found among the patients treated with tacrolimus ointment.
Similarly, there appears to be no evidence for an increased risk of
nonmelanoma skin cancers among the more than 5 million patients treated
with pimecrolimus 1% cream since it was released in the US market in
December 2001 (data on file, Novartis Pharmaceutical Co.).

[0024]The lack of clinical evidence of immunosuppression following topical
treatment of atopic skin with the calcineurin inhibitors is not
surprising, given their molecular size (>800 daltons). Because of
their size, the calcineurin inhibitors are unlikely to penetrate intact
skin to any significant extent. Furthermore, skin penetration of these
molecules will diminish as the inflammatory component of the atopic
disease resolves with therapy. By contrast, glucocorticosteroids, with
molecular weights<500 daltons, have the ability to penetrate both
normal and impaired skin and, as discussed earlier, represent a greater
threat to systemic absorption than do the calcineurin inhibitors. It is
not surprising that, in a 1-year study of adults with moderate to severe
atopic dermatitis treated with tacrolimus ointment, blood levels were
consistently found to be low..sup.[43] In this study,.sup.[47] 74.7% of
patients had no detectable levels of tacrolimus (<1 nanogram/mL) and,
in 16.8% of patients, blood levels were between 1 and 2 nanograms/mL. In
only 1 patient were levels in the range of a trough level for
immunosuppression (5.75 nanograms/mL) and, in this same patient, all
subsequent samples during the course of this 1-year study were<1
nanogram/mL..sup.[43] In adult patients with atopic dermatitis treated
with pimecrolimus 1% cream, systemic levels have been similarly low, the
highest level reported to date being 1.4 nanograms/mL (data on file,
Novartis Pharmaceuticals, Inc.).

[0025]Thus, given the lack of significant systemic exposure following
topical application of these medications, and given the lack of data in
humans linking the use of topical calcineurin inhibitors to B-cell
lymphoproliferative disorders or cutaneous malignancies, it is not
surprising that, in response to the FDA's announcement of its intention
to add a black-box warning to the labeling for these agents, the American
Academy of Dermatology stated that it was "disappointed that the FDA has
taken this action, despite the fact that there is no data that proves
proper topical use of pimecrolimus and tacrolimus is dangerous in
people.".sup.[48]

[0026]Other Topical Therapies

[0027]There have been few scientifically controlled trials of topical coal
tar in the treatment of atopic dermatitis..sup.[49] Given the cosmetic
unacceptability of coal tar, it is unlikely that most patients would
comply with treatment. Topical antipruritics should be used cautiously,
especially given the potential for the development of allergic contact
dermatitis when these agents are applied to inflamed and damaged skin.

[0028]Oral Antihistamines

[0029]Although sedating and nonsedating antihistamines are commonly used
in the management of AD, there is no evidence to support the efficacy of
nonsedating antihistamines..sup.[50] Regarding the reported improvements
in disease severity and quality of life following treatment with sedating
antihistamines, these effects could be driven by enhanced nocturnal
sleep, rather than as a result of reduction in symptoms..sup.[51,52]
Nonetheless, since many patients with atopic dermatitis have associated
rhinoconjunctivitis and/or dermatographism--and given the relative safety
profile of oral antihistamines--at least some patients with AD may
clearly benefit from oral antihistaminic therapy.

[0030]Systemic Therapies

[0031]Cyclosporine has been extensively studied in randomized controlled
trials for the treatment of severe atopic dermatitis in
adults..sup.[53-56] In these trials, patients experienced prompt relief
of symptoms; in some cases, the maximal response occurred within 2 weeks
of starting treatment..sup.[56] However, following cessation of therapy,
the majority of patients relapse within 6 weeks..sup.[55] The renal
toxicity and other systemic side effects of cyclosporine limit its
long-term usefulness in the treatment of AD.

[0032]Glucocorticosteroids, both oral and intramuscular, have been
commonly used in the treatment of refractory AD, reportedly with good
results..sup.[47] Surprisingly, there have been no randomized controlled
trials of systemic glucocorticosteroid therapy in the treatment of AD.
Due to side effects (including enhanced photocarcinogenicity with
systemic steroids, as reported in a study by Danes and
colleagues.sup.[48]) and issues related to tachyphylaxis and rebound
flares, systemic glucocorticosteroids should be used sparingly and only
to quell major flares of AD in adults.

[0035]Numerous studies in the literature support the role of broad-band
UVB,.sup.[59] narrow-band UVB,.sup.[60,61] PUVA,.sup.[62] and high-dose
UVA-1 therapy.sup.[63] in the treatment of atopic dermatitis. While PUVA
clearly increases the subsequent risk of squamous cell carcinoma, the
risks of skin cancers associated with UVB and high-intensity UVA-1 appear
to be low, on the basis of more than 75 years of data in patients treated
with UVA and UVB for psoriasis. Although they are potentially safer
alternatives to systemic therapy for adult AD, these modalities do have
their limitations. Chief among them are the severe lifestyle restrictions
of having to travel to a treatment center multiple times per week.
Furthermore, the patient's copayment for these treatments under many
managed care plans may range from $15-$30 per treatment, making the costs
of therapy prohibitive for some patients.

[0036]Systemic and Topical Antibiotics

[0037]Many individuals with AD are colonized with Staphylococcus aureus in
both affected and nonaffected skin..sup.[64,65] Although oral antibiotics
can be beneficial in the presence of impetigo and/or other cutaneous
bacterial infections, there is little evidence to support the use of
antibiotics, either topically or orally, in clinically uninfected
AD..sup.[66-68]

[0038]Miscellaneous Therapies

[0039]There is little scientific evidence to support the use of dietary
supplements, including treatment with fish oil, primrose oil, antioxidant
vitamins, or zinc. Herbal supplements have not been found to improve AD
in placebo-controlled trials, and concerns about toxicity are an issue.
The roles of hypnotherapy/biofeedback and other relaxation techniques
have yet to be proven.

CONCLUSION

[0040]The above treatments require long periods of therapy (up to 26
weeks) and are often only palliative in that there is a reduction in
symptoms such as itching. Once the treatment is terminated the lesion
often remains or returns and the itching returns when the medication
wears off. In addition the ingdence of side effects for the more
aggressive treatments such as systemic glucocorticoid steroids and the
Calcineurin Inhibitors can be so severe that treatment has to be
discontinued.

SUMMARY OF THE INVENTION

[0041]The AD irritation is characterized by itching, appearance of red and
rough skin. After application of the preparation the itching stops and
the redness recedes. The skin returns to its nearly normal condition
within 2-5 days. In the cases treated to date the lesion does not return
for at least 8-18 months or until exposure to the causative agent
reoccurs. In the prior art, weeks of treatment are required and in many
cases reduction in the itching occurs but the lesion does not disappear
and the itching returns.

[0042]Contrary to the above teachings that the symptoms of AD can be
controlled by the use of either topical glucocorticoid or oral
antihistamines when used individually, it has been found that the topical
use of glucocorticoid steroid and an antihistamine in combination at a
fixed ratio and in particular when the antihistamine has a high intrinsic
activity results in relief of the itching and rapid disappearance of the
lesion usually within 2-5 days whereas the prior art required weeks of
treatment which often resulted in the appearance of side effects which if
severe enough required the discontinuation of treatment.

[0043]The invention provides a topically administrable formulation for the
treatment of atopoic dermatitis in a mammal affected therewith having
active ingredients consisting essentially of at least one antihistamine
in its nonionized form or as the pharmaceutically acceptable salt thereof
and at least one compound selected from the group consisting of
corticosteroids and glucocortico steroids, formulated in a
pharmacologically acceptable carrier. Suitably the active ingredients are
dissolved in said carrier. The carrier may be a polar solvent and may
additionally comprises a non polar solvent, it may then additionally
comprise an emulsifying agent.

[0044]The formulation of may be administrable as a pump spray, an aerosol
spray or a foam. Where appropriate a propellant may also be present. It
may also be administrable as an ointment.

[0045]It has been found useful that the antihistamine in its nonionized
form or as the pharmaceutically acceptable salt thereof salt comprises
between about 0.001 and about 5.0 wt % of the entire formulation and the
corticosteroid or glucocortico steroid component comprises between about
0.001 and about 5.0 wt % of the entire formulation. Suitably, the
antihistamine comprises between about 0.01 and about 5.0 wt % of the
entire formulation.

[0046]While by no means limited thereto, the antihistamine is suitably
selected from the group consisting of clemastine, chlorpheniramine,
triprolidine, dextromethorphan, citirizine, fexofenadine, montelukast,
diphenhydramine and doxylamine in the nonionized form or as the
pharmaceutically acceptable salt thereof. It may also be selected from
the group consisting of astemizole, loratadine, and desloratidine in the
non-ionized form.

[0048]The Invention further provides method of treating atopic dermatitis
in a mammal afflicted with same, by applying active ingredients
consisting essentially of at least one antihistamine in its nonionized
form or as the pharmaceutically acceptable salt thereof and at least one
corticoid or at least one glucocortico steroid to the afflicted skin
areas thereof. The antihistamines and steroids are suitably, but not
limited to, those listed above. In this method the active ingredients may
be applied as a mixture or substantially contemporaneously.

[0049]While by no means limited thereto, the effective antihistamines,
most suitably, clemastine or chlorpheniramine in combination with
effective corticosteroids most suitably, triamcinolone actonide,
fluocinonide, or betamethasone dipropionate can be delivered to the site
of the lesion either as an ointment to be massaged into the skin by hand,
or as a spray or foam also to be massaged into the skin by hand. If a
salt is to be used, a pump spray and polar solvents would be preferred.
If the free base should be used as the active ingredient, either a pump
spray or foam, or an aerosol spray or foam using a propellant can be
employed. After applying the spray, foam or ointment, the resulting fine
layer of liquid can be massaged into the skin by hand. The use of the
word ointment is intended to included gels and creams.

[0050]The only limit on the solvents to be used for the spray, foam or
ointment is that they must be compatible with topical applications, and
at least one of them should have the properties of a dermal penetration
enhancer. These ointments can be packaged in foil packs or in tubes for
one time use or in larger containers for multiple uses.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051]Formulation of spays for Topical Application

[0052]In the preferred embodiments of the present invention there are
provided spray composition for topical administration of
antihistaminically active compounds and corticosteroids or a
glucocorticoid where these active compounds are soluble in a
pharmacologically acceptable polar solvent, the spray comprises, in
weight % of total composition: polar solvent 90-99.9%, active compounds
0.002-10%. In some cases a mixture of polar and non-polar solvents can be
used as long as a homogenous solution is obtained

[0053]Where the active compounds are soluble in a pharmacologically
acceptable non-polar solvent the spray composition comprises in weight %
of total composition: a pharmaceutically acceptable propellant, 45-93%,
non-polar solvent 5-55%, and active compounds 0.002-10%. In some cases a
mixture of polar and non-polar solvents can be used as long as the
combination is compatible with the propellant such that a homogenous
solution is obtained.

[0054]While the invention is in no way limited thereto, as active
antihistamines clemastine, chlorpheniramine, astemizole, triprolidine,
hydroxyzine, dextromethorphan, citirizine and loratadine in their
nonionized form or as the pharmaceutically acceptable salts thereof, have
been found most suitable.

[0055]While the invention is in no way limited thereto, as active
corticosteroid or glucocorticoid betamethasone dipropionate or valerate,
triamcinolone acetonide, fluocinonide, alclometasone dipropionate,
fluocinolone acetonide, clobetasol propionate, flurandrenolide,
monetasone furoate, hydrocortisone butyrate, halobetasol propionate have
been found most suitable.

[0056]Additionally, the topical spray compositions may comprise, by weight
of total composition: aromatizing agent 1-10%, suitably synthetic or
natural oil of peppermint, oil of spearmint, rose oil, citrus oil, fruit
aromas, perfumes and aromas commonly used in ointments and lotions and
combinations thereof.

[0057]As preferred polar solvents there may be mentioned low molecular
weight polyethylene glycols (PEG) of 200-600 MW, C2-8 mono- and
polyalcohols, and alcohols of C7-8 hydrocarbons of a linear or
branched configuration. Most suitable in this group are polyethylene
glycol and ethanol.

[0058]As non polar solvents, there may be utilized (C2- fatty
acid(C2-6)esters, (C7-18)hydrocarbons of a linear or branched
configuration, and (C2-6)alkanoyl esters, and triglycerides of said
fatty acids. Most suitably, miglyol.

[0059]A combination of polar and non-polar solvents can be used as long as
they are compatible with the propellant such that a homogenous solution
is obtained at 0-40 degrees C.

[0060]There are also provided lotion compositions, including ointments,
creams, emulsions and the like, for topical administration of
antihistaminically active compounds in combination with a corticosteroid
or glucocorticoid such as the general group and preferred species listed
above, wherein the composition comprises in weight % of total
composition: solvent 75-99.99%, active compounds 0.002-10%.

[0061]If desired, the foregoing aromatizing agents may also be used. As
solvents, the polar and non polar solvents listed above are also
operative.

[0062]The occurrence of atopic dermatitis in a mammal may be modified or
relieved by administering an antihistaminically pharmacologically active
compound in combination with a corticosteroid or glucocorticoid to said
mammal having been exposed to a atopic dermatitis causing substance, by
spraying the potentially affected skin location thereof with any of the
forgoing spray compositions, or applying any of the foregoing lotion
compositions.

[0063]Drug Substance Properties:

[0064]Antihistamines which may be used are limited to those that exhibit
antihistamine properties and that are soluble enough in the solvent of
choice to lead to solutions having a concentration of 0.001-5% w/w.
Suitably, there may be used clemastine, chlorpheniramine, astemazole,
triprolidine, dextromethorphan, citirizine and loratadine in their
nonionized form or as the pharmaceutically acceptable salts thereof. The
antihistamine of choice would be clemastine hydrogen fumarate or
clemastine base. A second first choice would be chlorpheniramine
hydrochloride or base. Corticosteroids and glucocorticoids which may be
used are limited to those that exhibit anti inflammatory and antipruritic
properties and that are soluble enough in the solvent of choice to lead
to solutions having a concentration of 0.001 to 5.0% w/w. Suitably, there
may be used betamethasone dipropionate or valerate, triamcinolone
acetonide, fluocinonide, alclometasone dipropionate, fluocinolone
acetonide, clobetasol propionate, flurandrenolide, monetasone furoate,
hydrocortisone butyrate, halobetasol propionate.

[0065]The preferred polar solvent properties are as follows: For salts and
such polar drugs, one can use water, low molecular weight alcohol's
(preferable ethanol), polyethylene glycols (PEG) in the range 200-600,
low molecular weight ketones such as acetone and combinations thereof. At
least one of the solvents acts as a dermal penetration enhancer.

[0066]The preferred non-polar solvent properties may be expressed as
follows: Non-polar, C7-18 hydrocarbons and their alcohols, esters of
fatty acids, fatty acid triglycerides such as migylol, must be miscible
with the propellant such that one phase is formed at temperatures
0-40° C. One of the solvents acts as a dermal penetration
enhancer.

[0067]In the case of a foam formulation, the composition comprises an oil
and water combination emulsified using an emulsifying agent commonly
known in the art. Hence both a polar and non-polar solvent will be
required.

[0068]Optionally, there may be employed aroma agents such as: oil of
peppermint, oil of spearmint, oil of wintergreen, citrus oils, both
synthetic and natural as well as oil of rose or other perfumes which are
normally used in creams and lotions.

[0069]A pump spray of the invention comprises the following formulation:

A metered dose valve is preferred so that a measured amount of the
preparation is deposited on the site.

[0070]Formulation of Foams for Topical Application

[0071]Foams can be formulated as is common in the art usually as oil/water
emulsions and as such use the above solvents as well as emulsifying
agents to maintain the mixture as an emulsion. These foams can be
delivered to the site of the atopic dermatitis either in a pump or
aerosol delivery system. In either case a metered dose valve is preferred
so that a measured amount of the preparation is deposited on the site.

[0074]The preferred Solvent Properties for the Solution Formulation are:
Solvents such as polyethylene glycols (PEG) of the 200-1000 molecular
weight, but preferred are those in the 200-600 range, fatty acid esters
and triglycerides. Low molecular weight alcohols and poly-alcohols can
also be used. One of the solvents acts as a dermal penetration enhancer.
If the ointment or gel is packaged as a soft gelatin capsule, glycerin
and water should be used sparingly as they will migrate into the shell
and weaken the shell or make it tacky.

[0075]Optionally Aroma Agents may be employed such as: Oil of peppermint,
oil of spearmint, oil of wintergreen, citrus oils, both synthetic and
natural. Oil of rose or other perfumes normally used in creams and
lotions may be used.

[0076]An ointment of the invention comprises the following formulation:

[0078]1 or 2 activations of 50 micro liters each would be used to deliver
a therapeutic amount of the combination to lesion of moderate size
(3×6 cm in area)

[0079]In accordance with the above formulation, but where, in place of
clemastine hydrogen fumarate there is utilized chlorpheniramine maleate,
astemizole, triprolidine hydrochloride, dextromethorphan hydrobromide,
citirizine hydrochloride or loratadine, and in place of triamcinolone
acetonide there is used betamethasone dipropionate or valerate,
fluocinonide, alclometasone dipropionate, fluocinolone acetonide,
clobetasol propionate, flurandrenolide, monetasone furoate,
hydrocortisone butyrate or halobetasol propionate, or fluocinonide, a
spray of similar activity is obtained, however actual dosage amounts of
the active substance as well as the amounts of solvents will vary.

[0081]1 or 2 drops of approximately 50 micro liters each would be used to
deliver a therapeutic amount of the combination to lesion of moderate
size (3×6 cm in area)

[0082]In accordance with the above formulation, but where, in place of
clemastine hydrogen fumarate there is utilized chlorpheniramine,
astemizole, triprolidine, dextromethorphan, citirizine and loratadine,
and in place of betamethasone dipropionate there is used betamethasone
valerate, fluocinonide, alclometasone dipropionate, fluocinolone
acetonide, clobetasol propionate, flurandrenolide, monetasone furoate,
hydrocortisone butyrate, halobetasol propionate, triamcinolone acetonide,
or fluocinonide, a ointment of similar activity is obtained, however
actual dosage amounts of the active substance as well as the amounts of
solvents will vary.

[0084]Treatment of atopic dermatitis with composition of Example 2. On Day
1 subject was diagnosed by his physician as having atopic dermatitis on
his back. The physician prescribed a topical corticoid steroid
(betamethasone propionate) which the subject applied several times a day
to relieve itching. After one week with no improvement in the scope of
the lesion or intensity of the itching once the effect of the ointment
wore off, the subject applied a topical antihistamine and again the
itching was relieved but after a week the lesion was unchanged. On Day 15
the subject applied a combination product of Example 2 to the site and
again the itching was relieved and after 4 days of treatment the lesion
regressed and the skin returned to a normal condition. There was no
relapse as of 18 months.